PROJECT SUMMARY 5 fluorouracil (5FU) has been the first choice chemotherapy drug for colorectal cancer (CRC) for many years; however, its clinical utility remains hampered by hematopoietic and gastrointestinal toxicities resulting from its non-selectivity. Emerging evidence suggests that the gut microbiota may influence the outcome of cancer therapy indicating a role for gut bacteria in the response to chemotherapy. Emodin, a natural anthraquinone derivative found in various Chinese medicinal herbs may increase the efficacy and reduce the toxicity of chemotherapy agents. Further, emodin has been reported to reduce the number of harmful bacteria and augment the number of beneficial bacteria in association with a reduction in toxins in a model of renal injury. The scientific premise for my study is that if emodin can modulate the gut environment it may increase the efficacy and reduce the toxicity of 5FU in CRC. The long-term goal is to increase the efficacy of chemotherapeutic drugs using complementary and integrative approaches. The objective in this particular investigation is to determine the benefits of emodin on increasing efficacy and decreasing toxicity of 5FU chemotherapy. The central hypothesis is that emodin induces changes in the gut environment that leads to increased efficacy and reduced toxicity associated with 5FU chemotherapy in CRC. I will test this hypothesis in two related specific aims: 1) determine the effects of dietary emodin on increasing efficacy and reducing toxicity of 5FU chemotherapy in CRC; and 2) determine whether emodin?s actions on 5FU chemotherapy in CRC are mediated by changes in the gut microbiota. Under the first aim, I will test the hypothesis that emodin can increase the efficacy and reduce the toxicity of 5FU in CRC. Using a chemically-induced mouse model of CRC, I will test the effects of emodin in combination with 5FU on tumorigenesis. Further, I will determine the effects of the combination treatment on behavioral outcomes including physical activity and pain measures. Finally, I will determine the benefits of emodin on mitigating the inflammation and mucositis that have been associated with 5FU. In aim 2, I will test the hypothesis that the benefits of emodin on 5FU in CRC are mediated by changes in the gut microbiota. I will test the effects of emodin on mitigating the effects of 5FU on gut microbiota. I will transfer gut microbes from 5FU treated mice to non-treated mice and administer emodin (or vehicle) to determine the perturbations associated with 5FU induced changes in the microbiota and whether emodin can mitigate these effects. Finally, I will use antibiotics and fecal transfer to determine whether emodin?s actions on increasing the efficacy of 5FU are mediated through alterations in the gut microbiota (increasing the colonization of commensal bacteria and/or reducing the number of harmful bacteria). This proposed preclinical study is significant as it will set the stage for clinical trials to develop emodin as a new complementary strategy for use with chemotherapy in CRC.